Leishmaniasis is an important neglected tropical disease that occurs worldwide and is caused by several different parasites with different characteristics. L. braziliensis infections are particularly distinct from other forms of leishmaniasis, since disease severity is not due to uncontrolled parasite replication, but rather to an exaggerated immune response. Thus, therapeutics designed to increase parasite killing are detrimental if they concomitantly enhance inflammatory responses. Our new data strongly suggests that optimal control of L. braziliensis requires a response that not only effectively eliminates the parasite, but also reduces the potential for immunopathology. In a series of publications, we have outlined the role of CD8 cytolytic T cells in driving inflammation by upregulating the inflammasome and inducing the release of IL-1?. Thus, our studies, and those of many other groups, indicate that an immunopathologic pathway involving the inflammasome and IL-1? production is a major driver of disease. Understanding the host and parasite factors driving this response will be important for designing new therapies. Another characteristic of this disease is that a high percentage of patients in the Northeast of Brazil fail treatment with the standard drug, meglumine antimoniate. We recently performed a large-scale transcriptional analysis of leishmanial lesions from L. braziliensis patients prior to drug treatment and found that treatment failure correlated with expression of genes associated with cytolysis and IL-1?. These striking results further demonstrate the significance of this CD8-inflammasome-IL-1? pathway in promoting disease, and we hypothesize that drug failure in patients is due to the magnitude of these pathologic responses. Another important aspect of our recent findings is that they allow us to predict, based on the expression of cytolytic genes, which patients will fail the standard treatment. We propose three specific aims to advance our understanding of inflammasome activation and develop a field-tested approach to predicting treatment failure. In Aim 1 we will define the cells and signals contributing to inflammasome activation in cutaneous leishmaniasis, using cells from lesions and blood of L. braziliensis patients and healthy subjects. In Aim 2 we will determine the role of L. braziliensis isolates in disease development. And, in Aim 3 we will assess the ability to predict treatment failure in a clinical setting. Taken together, these studies will provide new information about this disease that can be translated into new therapies, as well as a practical field-testing approach to predicting treatment failure.